Disruptors of early/recycling endosomes

Abstract

A delivery system for introducing a cargo molecule into cytosol of a living cell can include: a first membrane binding element linked to an endosomal compartment disrupting element through a first linker having one or more anionic moieties; and a second membrane binding element linked to an exogenous cargo molecule through a second linker having one or more anionic moieties, the second linker having a region that is selectively cleavable, wherein the first and second membrane binding elements both induce endocytosis into an early / recycling endosome and the endosomal compartment disrupting element destabilizes the early / recycling endosome such that the exogenous cargo molecule is released from the second membrane binding element and into the cytosol of the living cell.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This patent application claims benefit of U.S. patent application having Ser. No. 61 / 089,710, filed on Aug. 18, 2008, which provisional application is incorporated in its entirety by specific reference.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]This invention was made with government support under CA-83831 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND OF THE INVENTION[0003]It is often difficult to deliver compounds, such as proteins, peptides, nucleic acids and other drugs and diagnostic compounds intracellularly because cell membranes resist the passage of these compounds.[0004]One method for transmembrane delivery of exogenous molecules is based on the mechanism of receptor-mediated endocytosis (RME). RME is a major mechanism of uptake of impermeant molecules by mammalian cells. In this process, extracellular ligands bind cell surface receptors that ...

AI Technical Summary

Benefits of technology

The present invention provides a delivery system for introducing a cargo molecule into cytosol of a living cell. The system includes a membrane binding element, an endosomal compartment disrupting element, and a selectively cleavable region that is cleaved by an endosomal protease or a substance preferentially located in cytosol. The membrane binding element induces endocytosis of the delivery system into an early / recycling endosome that acidifies to induce the endosomal compartment disrupting element to destabilize the endosome and release the cargo molecule into the cytosol. The delivery system can be used to deliver various cargo molecules, such as drugs, prodrugs, molecular probes, and proteins, into living cells for therapeutic or research purposes.

Problems solved by technology

It is often difficult to deliver compounds, such as proteins, peptides, nucleic acids and other drugs and diagnostic compounds intracellularly because cell membranes resist the passage of these compounds.

Nevertheless, many exogenous molecules that are introduced into cells using RME are not able to escape degradation in the late endosomes or the lysosome.

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